2nd Joint Annual Meeting – Club Phase I and AGAH Positioning Human Pharmacology for the Future Bad Homburg v.d.H., April 26 and 27, 2007 H. W. Seyberth Department of Pediatrics Philipps University, Marburg/Germany Workshop: Workshop: esigns of human pharmacology trials fo esigns of human pharmacology trials fo paediatric populations paediatric populations
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2nd Joint Annual Meeting – Club Phase I and AGAH Positioning Human Pharmacology for the Future Bad Homburg v.d.H., April 26 and 27, 2007 H. W. Seyberth.
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2nd Joint Annual Meeting – Club Phase I and AGAHPositioning Human Pharmacology for the Future
Bad Homburg v.d.H., April 26 and 27, 2007
H. W. Seyberth
Department of Pediatrics
Philipps University, Marburg/Germany
Workshop: Workshop:
Designs of human pharmacology trials forDesigns of human pharmacology trials for
paediatric populationspaediatric populations
Physiology, Diseases and
Developmental Pharmacology
Appreciation of at least
five phases
of development
Physiology:
Large body surface Increased skin permeability Reduced surfactant synthesis
Aortopulmonary shuntsImmaturity of the brain stem No ciruclatory autoregulation Incomplete retinal vascularisation
Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation
Pathophysiology:
Respiratory distressPulmonary hypertensionPatent ductus arteriosusApneaIntraventricular hemorrhageRetinopathy of prematurity (ROP)Bronchopulmonary dysplasia
Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation
Term Newborn: Phase of Adaptationage: birth up to 1 month
Physiology:
Large body surfaceIncreased skin permeabilityIncreased body water Decreased blood brain barrierIncomplete neuronal maturationIncreased hemolysis
dosis:0.05 mg/kg/min infusionrate until painlessness
Indomethacin induces GFR reduction in young adults with volume depletion and in preterm infants with sPDA
GF
Rm
l/min
/1.7
3m2
2 mg/kg/d
0.2 mg/kg/d
91
19.5
- 12 %
- 40%
adults infants
8080
60
40
20
100
11.7
without indo
with indo
Congenital salt losing tubulopathies (SLTs)Congenital salt losing tubulopathies (SLTs)Different aDifferent age at manifestation and ontogeny of targets ge at manifestation and ontogeny of targets (Jeck et al., AJ P 2005)(Jeck et al., AJ P 2005)
Adverse effects of geriatric heart failure therapy Adverse effects of geriatric heart failure therapy applied to preterm infants with sPDA:applied to preterm infants with sPDA:
arrhythmias with cerebral bleeding
marked volume depletion renal hypoperfusion
PG-stimulationnephrocalcinosis
intestinal perforationrenal failure
Pre-renal failure in the preterm infant with sPDAPre-renal failure in the preterm infant with sPDA
filtration
v. afferens v. efferens
vasodilation vasoconstrictionprostaglandins angiotensin II
Examples on long-term adverse effects of medicines in early infancy and childhood